The consolidation of remote memories relies on both synaptic consolidation processes on the timescale of minutes to hours, and circuit consolidation over weeks to years (Frankland and Bontempi, 2005; Squire and Bayley, 2007). The process of long-term contextual fear memory consolidation requires early involvement of the hippocampus, followed by the neocortex; in the course of this process, an influence of hippocampus on neocortex may enable the hippocampus to facilitate the long-term cortical storage of memory, rather than stably store the memory itself. Studies have shown that hippocampal lesions impair recent memory one day after training, but the same lesions had no effect on remote memory, several weeks after training (Anagnostaras et al., 1999; Bontempi et al., 1999; Debiec et al., 2002; Frankland et al., 2004; Kim and Fanselow, 1992; Kitamura et al., 2009; Maren et al., 1997; Maviel et al., 2004; Shimizu et al., 2000; Wang et al., 2003; Winocur et al., 2009). Additional studies suggest that both hippocampal and cortical memories are in continuous interplay.
Previous work on the circuitry of memory has involved physical, pharmacological and genetic lesion studies, which have greatly enhanced our understanding of neural systems but also have suffered from certain well-known challenges; for example, physical lesions are highly effective but lack both cellular and temporal precision, and other methods typically involve tradeoffs between cellular and temporal precision. Elegant genetic interventions can be cell-type specific (McHugh et al., 2007; Nakashiba et al., 2008), but are slow on the timescale of days. Pharmacological lesions enable higher temporal resolution on the timescale of minutes (Kitamura et al., 2009; Wiltgen et al., 2010), but are still slower than neurons and not typically cell-specific. There is a need for developing methods and tools that enable both cell-type precision and temporal control on the millisecond timescale for the study of memory in animals.
Various psychiatric conditions may arise due to a disorder in the circuitry of memory. For example, amnesia (e.g., non-graded, graded retrograde, focal retrograde amnesia, etc.) involves an inability to retrieve certain memories, while post traumatic stress disorder (PTSD) involves undesired retrieval of fearful memories. PTSD is a common debilitating psychiatric condition in which a single exposure to a traumatic event can lead to years of compromised function due to repeated re-experiencing of the trauma. Understanding the neural pathways that underlie undesired memory recall may help aid in the discovery and screening of pharmacological therapies to treat patients with such memory disorders.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.